Familial erythrocytosis is a set of genetic conditions characterized by an increased content of hemoglobin and erythrocytes in the blood, which leads to a violation of its rheological properties. Symptoms of pathology, depending on its severity, may include headaches, cardiac arrhythmias, hemorrhages, thrombotic disorders, cyanosis or, conversely, a crimson tint of the skin and mucous membranes. Diagnosis is made on the basis of laboratory blood tests and physical examination of the patient. Molecular genetic methods for determining the disease have been developed for some forms. There is no specific treatment for most forms of hereditary familial erythrocytosis, symptomatic and supportive therapy is used.
Familial erythrocytosis is a group of hereditary diseases in which, for one reason or another, the production of hemoglobin and red blood cells in the body sharply increases. This violation is quite common, the occurrence of various forms ranges from 1:10,000 to 1:100,000. The disease must be differentiated from acquired forms of erythrocytosis and true polycythemia. Among the various types of familial erythrocytosis, there are forms with different types of inheritance – both autosomal dominant and autosomal recessive. The latter, as a rule, have a more severe course and in some cases can lead to death even in childhood. The sexual distribution of most types of pathology has no peculiarities – men and women suffer from it equally often. Among some ethnic groups (in particular, among the Chuvash), there is an increased frequency of this disease. For a number of forms of familial erythrocytosis, key genes have not yet been identified, so their etiology and pathogenesis remain unclear.
Causes and classification
All forms of familial erythrocytosis can be divided into several groups, taking into account the causes of development: caused by mutations of hemoglobin genes, provoked by metabolic disorders in erythrocytes and caused by abnormally high production of erythropoietin by the kidneys.
Familial erythrocytosis caused by mutation of hemoglobin genes localized on the 16th and 11th chromosomes. As a result of mutations, the affinity of this protein to oxygen increases or the valence of the iron ion in the heme changes. Oxygen coming from the lungs is stronger than that of a healthy person, binds to hemoglobin and is more difficult to transport into tissues, which causes hypoxia. There is a reaction from the juxtaglomerular apparatus of the kidneys, which begins to intensively produce the hormone erythropoietin, which stimulates the formation of a large number of red blood cells in the red bone marrow. An example of such a variant of familial erythrocytosis can be congenital M-hemoglobinopathy. In total, more than 130 variants of the abnormal structure of hemoglobin caused by such mutations have been identified, of which several dozen are capable of leading to hereditary familial erythrocytosis – in most cases these are autosomal dominant pathologies with a relatively benign course.
Familial erythrocytosis, provoked by metabolic disorders in the erythrocytes themselves. The functioning of hemoglobin and its affinity for oxygen depend not only on the structure of this protein, but also on a number of auxiliary factors (the presence of certain enzymes, the level of ATP). In particular, a deficiency of 2,3–diphosphoglycerate phosphatase (an enzyme that catalyzes the hydrolysis of 2,3-diphosphoglycerate, a compound that increases the affinity of hemoglobin to oxygen) or an increased level of ATP can lead to hereditary familial erythrocytosis. The main link in the development of the disease is an increase in oxygen binding by erythrocytes. In the future, pathogenesis follows the same path as in the previous group of pathologies. Most often these are autosomal recessive diseases with sufficiently pronounced symptoms and severe course.
Familial erythrocytosis caused by the primary abnormally high release of erythropoietin in the juxtaglomerular apparatus of the kidneys. The cause of the disorder may be various genetic defects that affect the sensitivity of kidney receptors to hypoxia. The most studied variant of this type of hereditary familial erythrocytosis is caused by a mutation of the VHL gene localized on the 3rd chromosome and is a suppressor of tumor growth. Its defect also leads to the development of Hippel-Lindau syndrome. Familial erythrocytosis caused by the VHL mutation has at least two phenotypic forms and is transmitted by an autosomal recessive mechanism.
Manifestations of familial erythrocytosis and their severity vary widely depending on the form and cause of the disease. The types of disease caused by pathological forms of hemoglobin are usually more easily tolerated – pronounced symptoms occur more often in adolescence or adulthood, cyanosis and headaches are observed in patients, occasionally there may be interruptions in the work of the heart (especially during physical exertion). Often, these forms of hereditary familial erythrocytosis are asymptomatic and are accidentally detected when a general blood test or other medical studies are prescribed. However, some forms of abnormal hemoglobin have such a high affinity for oxygen that they lead to significant oxygen starvation of tissues and subsequent erythrocytosis.
Familial erythrocytosis type 2, caused by metabolic disorders in erythrocytes, has a brighter clinical course. As a rule, pathology is diagnosed in early childhood. Characteristic symptoms are red cyanosis of the skin, severe headaches, shortness of breath during exercise, tachycardia and heart failure. In a number of patients with such forms of hereditary familial erythrocytosis, varicose veins of the lower extremities and rectum (hemorrhoids) are determined. An enlargement of the liver and spleen (hepatosplenomegaly), a change in the shape of the distal phalanges of fingers and nails (“drumsticks”, “watch glasses”), bleeding gums and frequent nosebleeds are often detected. Numerous hemorrhages are found on the skin. Strokes and infarctions of various organs caused by thrombotic disorders can be diagnosed.
With other causes of familial erythrocytosis, in particular, with mutations of the VHL gene, an even more severe course of the disease is observed. There are two clinical varieties of pathology of this type – severe and moderate. The first is characterized by early onset (up to 5-8 years), low blood pressure, pronounced red cyanosis of the skin and mucous membranes, frequent bleeding. The second has a more benign course, occurs in children older than 8-9 years or in adolescents, cyanosis and bleeding are much less pronounced. For the form of pathology caused by the VHL defect, signs of oxygen starvation of tissues (shortness of breath, change in the shape of fingers and nails) are uncharacteristic, since the affinity of hemoglobin to oxygen does not change. Headaches and heart disorders are possible due to an increase in the volume of circulating blood.
Due to the polyethologicity of familial erythrocytosis, a huge number of different techniques are used to diagnose this condition. The primary determination of erythrocytosis is carried out on the basis of a general blood test, to clarify the causes and type of pathology, additional research methods may be required: hemoglobin electrophoresis, determination of erythropoietin levels, molecular genetic techniques (performed by a geneticist), study of the patient’s hereditary history. To exclude acquired or secondary forms of erythrocytosis, studies are conducted aimed at studying the work of the kidneys, heart and lungs, and a red bone marrow biopsy is performed.
A general blood test reveals a significant increase in the amount of hemoglobin and red blood cells, their color indicators are usually within the normal range or slightly lowered with a lack of iron. With familial erythrocytosis, hematocrit increases significantly, in some cases reaching a value of 90% – the phenomenon has received the conditional name “solid blood”. Sometimes there is a slight decrease in the level of other shaped elements of the blood, which is due to the proliferation of red bone marrow germ. Bone marrow biopsy reveals hyperplasia of the erythroid germ, which, in the absence of pathologies of the kidneys, heart and lungs, also indicates hereditary familial erythrocytosis.
During electrophoresis, abnormal forms of hemoglobin with increased affinity for oxygen can be detected, and a high level of erythropoietins is almost always observed. A general examination and other instrumental examinations can reveal cardiac outages, varicose veins and increased intracranial pressure due to hypervolemia. Molecular genetic analysis is currently performed only for forms of hereditary familial erythrocytosis caused by a mutation of the VHL gene. In other cases, a hereditary history is used to clarify the diagnosis and determine the type of inheritance.
Treatment and prognosis
There is no specific treatment for hereditary familial erythrocytosis, symptomatic therapy is used. To reduce the likelihood of developing thrombotic complications of the disease, antiplatelet agents and other similar agents are used – for example, acetylsalicylic acid. In more severe cases of hereditary familial erythrocytosis, anticoagulants (heparin, warfarin and their analogues) may be required. Previously recommended bloodletting in recent years has become the object of criticism by specialists, since regular blood loss stimulates the bone marrow, and the effect of such procedures is becoming more and more short-lived. Cytotoxic therapy for hereditary familial erythrocytosis can significantly improve the condition of patients, but it should be prescribed with caution.
The prognosis of most forms of familial erythrocytosis is relatively favorable, especially with varieties of the disease caused by the presence of abnormal hemoglobin. Often such pathologies are asymptomatic. More severe autosomal recessive forms of hereditary familial erythrocytosis can lead to the death of the patient due to bleeding and thrombotic disorders (myocardial infarction, kidney, lung, stroke, thromboembolism). Sometimes there are neurological disorders caused by hypervolemia and increased intracranial pressure – in children this can cause mental retardation and dementia.
As with many other genetic diseases, there is no clear system of prevention of familial erythrocytosis. Prenatal genetic diagnosis is possible for some forms. Medical and genetic counseling of parents before conception is carried out to identify the carrier of the defective form of the VHL gene. With an already confirmed diagnosis of hereditary familial erythrocytosis and finding out its causes, regular monitoring by a hematologist is necessary to prevent possible complications, prescribe symptomatic and supportive treatment. In the presence of secondary disorders (from the nervous system, heart, kidneys), consultations of specialized specialists may be required.